DBA-RegisterKoordinierende Studienzentrale

DBA is caused by a malfunction of the ribosomes in cells. Ribosomes produce proteins by joining together amino acids (the building blocks for proteins). Ribonucleic acid (contains the genetic information of the DNA, also referred to as messenger-RNA or mRNA) acts as the construction manual or “master template” for the production of the various different proteins in the ribosome. mRNA “runs” through the ribosome when proteins are formed. This arranges the amino acids in the right sequence and connects them together. The resultant chain of amino acids (the protein) then exits the ribosome to perform its specific function (see Figure 1).

Ribosomes are composed of one large subunit and one small subunit. The subunits themselves are composed of proteins and ribonucleic acid (ribosomal RNA or rRNA). DBA is caused by various mutations (genetic alterations) that predominantly cause faults in the composition of the ribosomes (their proteins or ribonucleic acids).

This disruption in protein production in the ribosomes has major consequences since proteins carry out many tasks that an organism requires to survive. All human nucleated cells, which include the haematopoietic (blood-producing) cells in bone marrow and bone cells, produce and contain proteins which they also use to communicate. Proteins also transport essential substances. An example is haemoglobin (the red pigment in blood) which transports oxygen inside the body and carries it to the organs. Antibodies are also proteins which “label” foreign bodies, contributing to the body’s defence systems. There are numerous other proteins with many different functions that are essential for maintaining the body’s health. Since DBA is already present at the early stages of development in the womb it is easy to see why it may give rise to congenital malformations.

What is not yet understood is why DBA primarily manifests itself in bone marrow as disordered erythropoiesis and why the severity of symptoms varies so much between individual DBA patients, with symptoms completely absent in some cases.

Many mutations cause errors in the composition and functions of the components of the large or small subunit of ribosomes or other structures that are important for ribosome function.

The mutations causing DBA have been identified for approximately 70-80% of patients. They affect the proteins in the large subunit (ribosomal protein large, RPL) or small subunit (ribosomal protein small, RPS) of the ribosomes or more rarely other structures that are important for ribosome function. In most cases the mutations involve the replacement of one or a few nucleic acids in the gene. There are currently a total of 28 known mutations in ribosomal genes. In a small number of DBA patients whole parts of a chromosome with several different genes are missing (this is referred to as “deletion”), where one of the missing genes codes for a ribosome protein. Mutations in the genes for the proteins RPS19, RPL5, RPS26 and RPL11 are responsible for approximately 70% -80% of all known genetic alterations in people with DBA (see Figure 2).

The mutation that causes DBA can be inherited from a parent or may occur at an early stage of the embryo. As with many other illnesses, it is not yet known what causes or triggers the onset of these new mutations.

The mutations always affect all body cells and can be passed on to offspring. There is a 50% chance of passing on a DBA mutation to the next generation. This form of inheritance is called “autosomal-dominant” since inheriting a DBA mutation from just one parent is enough to trigger the disease in offspring.

Where several members of a family are affected by DBA they all have the same causal mutation. However the DBA symptoms of the family members affected may differ widely, ranging from no health problems at all to requiring transfusions. The reason for the differences in the presentation of the disease is largely unknown. Although generally the severity of DBA increases from generation to generation (“anticipation”), it is not possible to predict the severity of the disease for the individual carrier of a DBA-typical mutation.

All patients with DBA should be offered genetic counselling. Prenatal diagnostic testing (genetic diagnostic testing before birth) and pre-implant diagnostic testing (for in vitro fertilisation/artificial insemination) to identify a known DBA mutation in a parent are possible, but cannot predict the presentation and severity of the disease.

The health problems of patients with DBA are mainly due to decreased haematopoiesis in the bone marrow and the treatment this requires. Decreased erythropoiesis (the production of red blood cells) causes anaemia; in rare cases it also causes a decrease in the production of leukocytes (white blood cells) and/or thrombocytes (platelets). Associated malformations may require corrective surgery. Patients with DBA have an increased cancer risk. The level of this risk and its significance cannot currently be clearly stated. Organ damage may occur as a result of treatment for anaemia with blood transfusions. In the liver, the pancreas and myocardium in particular, damage may occur as a result of iron overload from blood transfusions; iron overload may also occur in non-transfused patients.

The blood system

Red blood cells, white blood cells and platelets are produced in the bone marrow. DBA can lead to decreased production in all three lineages (“pancytopenia”). Decreased erythropoiesis and the anaemia it causes are the main symptoms in almost all cases. The white blood cell count is slightly depressed in many DBA patients without any impact on their health.

Typical symptoms reported by patients with anaemia are increased pallor, palpitations, headache, fatigue, shortness of breath during physical exertion as well as poor appetite and failure to thrive in infants. Although infants in particular often appear to be relatively unaffected despite clearly being anaemic it is likely that anaemia will have an unfavourable impact on a DBA patient’s health in the long term. DBA patients should therefore be given consistent treatment for anaemia at every year of life.

Possible malformations

Around 40% of DBA patients have congenital malformations that can affect various different organs. Common malformations are those affecting the face, such as a cleft palate, or arms and the thumb. Heart defects, kidney deformities, inguinal hernias, congenital glaucoma or cataract, skin lesions such as large “liver spots” and developmental disorders may occur. Body length is at the lower end of the normal range for most DBA patients, with restricted growth in some patients.

Infants with DBA have been described as having a typical “DBA facies” with a snub nose, widely-spaced eyes, thick upper lip, deep-set ears and an alert expression. However these abnormalities appear to vanish as infants grow.

On the cancer risk

DBA patients have a higher risk of developing cancer in the course of their lifetime compared with their healthy peers. Currently it is not possible to provide an adequate assessment of the precise level of risk. In contrast to other congenital bone marrow disorders such as Fanconi anaemia, severe congenital neutropenia, Shwachman-Diamond syndrome, recent data reveal no increase in, or only a slightly increased, risk of the onset of leukaemia or a myelodysplastic syndrome (MDS). However, reports of diseases such as breast cancer, bowel cancer or other carcinomas have increased in recent years in young and middle aged DBA patients.

The data situation is currently not good enough to develop a general recommendation on the need for a cancer screening programme for DBA patients. Annual health check-ups by the GP or specialist, take-up of health screening and care measures available to the public and consulting a doctor if symptoms occur (diarrhoea, blood in stools, chest pain, changes in moles etc.), however, are explicitly recommended for all DBA patients, particularly in adulthood. Case reports show an increase in incidence of bone tumours (osteosarcoma) in children, adolescents and young adults, however early detection of these cancers is not currently possible.

Organ damage due to iron overload

Red blood cells transport oxygen in the blood. They contain haemoglobin which binds the oxygen via an iron molecule. The body responds to anaemia by attempting to increase erythropoiesis by, for example, increasing iron absorption from food in the gut. However, patients with DBA cannot metabolise this additional iron intake since haematopoiesis is impaired due to the ribosomal malfunction. Since the human body does not have a mechanism for eliminating the surplus iron, patients with DBA may develop iron overload spontaneously. The iron cannot be metabolised and is stored in the organs. Blood transfusions, which consist of red blood cells, add to the iron overload since red blood cells contain large amounts of iron.

Long-term iron overload causes damage to many organs, in particular the heart, liver and various hormone-producing glands such as the thyroid gland, the pituitary gland and the pancreas. Without adequate treatment, therefore, severe (sometimes fatal) complications may occur such as myocardial insufficiency and cardiac arrhythmias (cardiomyopathy), hepatitis and liver dysfunction, diabetes, restricted growth, delayed puberty, hypothyroidism and disorders of Vitamin D metabolism.

DBA patients with iron overload and/or patients regularly receiving blood transfusions are therefore given treatment with drugs that combine with the surplus iron so it can be eliminated via stools and urine.

If a patient is suspected of having DBA, a detailed medical history (anamnesis) and physical examination should be carried out first. The blood count is then tested by taking a blood sample. A haemoglobin assay and microscopic examination of the blood smear are used to determine whether anaemia is present, how severe it is and whether it is likely to involve DBA or is another type of anaemia.

The following tests are recommended if DBA is suspected:

• taking of individual medical history and family history

Explanation: A family history that is positive for DBA or unexplained anaemia during childhood may indicate DBA.

• physical examination

Explanation: Malformations may indicate the presence of DBA.

• blood count with differential count and reticulocyte count

Explanation: The red blood cells produced before birth have properties and components that are different from red blood cells produced after birth. Foetal red blood cells have a greater volume (mean corpuscular volume, MCV), a higher proportion of foetal haemoglobin (HbF) and a higher concentration of the enzyme ADA (see below). Red blood cells of DBA patients often exhibit properties similar to foetal cells.

• basic laboratory diagnostic tests with liver and kidney values, haemolytic parameters (laboratory parameters that are elevated when erythrocytes are destroyed), ferritin (measure of iron storages of body)
• measurement of haemoglobin F (HbF) levels in blood (before transfusion if possible)

Explanation: A number of different haemoglobins are produced as the foetus develops in the uterus. Shortly before birth the majority of the haemoglobin comprises haemoglobin F (foetal haemoglobin, HbF) which differs from the haemoglobin A (adult haemoglobin) that is produced later. In DBA patients the number of red blood cells containing HbF is increased.

• measurement of enzyme activity of the adenosine deaminase (ADA) in red blood cells (before transfusion if possible).

Explanation: The enzyme ADA plays an important role in metabolising deoxyribonucleic acid (DNA). There are high levels of ADA in red blood cells prior to birth. The red blood cells in DBA patients generally still exhibit properties that are otherwise only observed prior to birth. These include elevated HbF levels and increased ADA concentrations. Since a blood transfusion reduces the concentration of red blood cells produced by the body itself, HbF and ADA assays should if possible be conducted before transfusion or at a considerable interval since/until transfusion.

• bone marrow analysis for
  • morphological evaluation of bone marrow smears (see Figure 3)
  • chromosome analysis of bone marrow cells
  • exclusion of parvovirus B19 infection in bone marrow by polymerase chain reaction method (PCR)

Explanation: A bone marrow analysis is recommended for all DBA patients (even if the diagnosis has been confirmed by genetic testing). The morphological analysis of the bone marrow must be compatible with the diagnosis of DBA (reduction in number of red blood cell precursors) and acts (as does the chromosome analysis) as a baseline for other tests that may be required at a later point. Infection with parvovirus B19 (the pathogen that causes ringlets) may like DBA cause hypoplastic anaemia and can only be reliably excluded by a negative PCR in the bone marrow.

• molecular genetic diagnostic testing of all DBA-associated genes
  Explanation: A genetic alteration implicated in pathogenesis can now be identified in 70-80% of patients (mutation or deletion). The diagnosis of DBA is established when such a genetic alteration is detected. However, a diagnosis of DBA cannot be excluded if a genetic alteration is not found. It is possible that the results of the molecular genetic testing may be unclear (variants of unclear variance) or unexpected (incidental findings). Detailed informed consent is therefore required before the test.

The following supplementary tests are recommended if the DBA diagnosis is established:

• examinations to detect non-visible malformations: cardiac and abdominal ultrasound
• immunoglobulin assay and lymphocyte phenotyping
• determination of blood  group and antibody screening test as well as direct Coombs test

When a child or adult is diagnosed with DBA, further care should take place at a specialist centre for blood disorders. The DBA register also offers a face-to-face consultation for DBA patients and their families at any time.

The medical personnel at specialist centres are experienced in the treatment of patients with rare blood disorders such as DBA. It is important that patients attend such a centre regularly so that the course of the disease can be carefully monitored and complications identified and treated at an early stage. Questions on how to interact with the sick child, commonly used and novel treatment methods and the latest research findings can be answered by appropriately qualified professionals. All DBA patients should be offered counselling by a medical social worker and psychological support.

The type of treatment used for DBA depends on the severity of the signs of the disease and whether a response to a specific form of therapy is observed. Whereas many DBA patients require continuous treatment, some patients may manage phases or long periods without treatment. The following treatment options are available:

• regular blood transfusions (=red cell concentrates)
• administration of steroids (= cortisone, glucocorticoids)
• allogeneic stem cell transplantation (SCT)
• gene therapy (in the near future)
• individual, experimental treatments which have so far not been adequately validated in studies to qualify as recommended treatments
• treatment of malformations
• treatment of therapeutic sequelae, particularly iron chelation therapy

Blood transfusion

A blood transfusion involves administering red blood cells from a healthy blood donor. Red blood cells from a healthy donor are administered to patients through a needle into the vein (mostly in the elbow). This normally involves transfusing 10 - 15 mL red cell concentrate per kg of body weight (the volume of one bag of red cell concentrate is approx. 250 - 300 mL). Patients with DBA requiring transfusion usually receive a blood transfusion every three to six weeks. Where patients require regular transfusions these should be administered at fixed intervals, subject to a selected pre-transfusion haemoglobin level (target haemoglobin trough level). For children with DBA, the recommended pre-transfusion haemoglobin trough level is 9.5 - 10 g/dL. This allows the optimal conditions to be created for ensuring an adequate oxygen supply to the body is maintained, age-appropriate development in children and adolescents and the best possible quality of life in adulthood. Not all patients with DBA remain dependent on transfusions throughout their entire life.

The transfusing doctor will explain the risks of a blood transfusion. The risk of transmitting viral diseases (hepatitis B, C, HIV) through a blood transfusion is extremely low nowadays due to comprehensive screening of donors and blood products.

A range of tests are required to monitor therapy during regular blood transfusions (see Download section).

Steroids

Steroids, also known as glucocorticoids, are the body’s own hormones (messengers) that may stimulate haematopoiesis. Their precise mechanism of action in stimulation of haematopoiesis is still unclear. To treat DBA artificially produced steroids are used. However, since the substances also have a growth-inhibiting effect, they should be avoided as far as possible in children before their first birthday. The dose of steroids is related to the patients’ body weight.

In infants with DBA requiring transfusion, a trial course of steroids is recommended after the first birthday. In most cases, steroid treatment at a daily dose of 2 mg/kg body weight is started approximately 2 weeks after a transfusion (the maximum steroid dose in adults is 60 mg). Blood count is checked regularly during steroid trials. If the haemoglobin level increases or remains stable (without transfusion) the dose is then tapered. The minimum dosage required to maintain standard haemoglobin levels over the long term is then identified.

If haemoglobin levels decline significantly four weeks after the start of the steroid trial, it is considered unsuccessful and therapy is resumed with regular transfusions. A second (generally the last) trial course of steroids is then administered, in most cases 1 year later.

Steroid treatment is associated with acute and chronic side effects depending on the dose. Acute side effects such as increased appetite, weight gain, changes to shape of the face, mood swings, occasionally also elevated blood pressure and blood glucose levels are frequently reported at high doses (2 mg/kg body weight); these rapidly subside when the dose is reduced. Chronic side effects generally only occur at excessive dosages (above 0.2 - 0.3 mg/kg weight/day) and include blood glucose imbalance, changes to physique and skin, high blood pressure, impaired vision, growth retardation, bone weakness and gastritis. Long-term treatment with steroids should therefore not exceed dosages of 0.2 - 0.3 mg per kg body weight per day. Regular check-ups are also required during steroid treatment (see Download section).

Allogeneic stem cell transplantation

Allogeneic stem cell transplantation (SCT) is currently the only available therapy that cures the disease in the bone marrow and is thus a definitive treatment for anaemia. We recommend using bone marrow stem cells for SCT in children and adolescents; peripheral blood stem cells are a secondary option. Since SCT may have life-threatening and severe long-term side effects the risks and benefits of treatment must be considered on a patient-by-patient basis. There is now a very high chance of curing the anaemia with SCT subject to optimal preparation and patient selection. The risk of severe and fatal complications of SCT increases rapidly with age in DBA patients and SCT is mostly offered as a treatment option to children under 10 years requiring transfusion only if an optimal donor (sibling or matched unrelated donor) is available. We offer all families an information meeting about SCT following the failed first steroid trial.

Due to severe complications of transfusions, for example development of antibodies to red blood cells (alloimmunisation) making it impossible to continue blood transfusions, or uncontrollable side effects of drugs for iron chelation, SCT may also be necessary for older DBA patients. A permanent drop in white blood cell count (causing infections) or platelet count (cannot be permanently replaced by transfusions) may also justify SCT. In older children (>10 years) and adults, only very experienced treatment teams should review whether SCT is indicated.

Gene therapy

Gene therapy is already being used successfully in studies for another bone marrow disease, Fanconi anaemia. Gene therapy-based treatments are also likely to be offered for DBA in a few years. In gene therapy, fresh haematopoietic stem cells must first be harvested from patients. This is achieved by administering a drug to induce the stem cells to leave the patient’s bone marrow and enter the blood stream and separating the blood into its various components outside the body using a device known as a leukapheresis unit (similar to haemodialysis). Specific carriers (“vectors”) are then used to introduce a healthy gene into the stem cells to replace the defective gene(s) (“transduction”), or the defective gene is corrected (“genome editing”). This allows the genetic defect to be removed and the ribosome malfunction reversed. Gene therapies are so far being developed for the RPS19 gene.

Individual treatment options which have so far not been adequately validated in studies to qualify as recommended treatments

A whole series of other drugs have been trialled for treatment of DBA patients, including intravenous immunoglobulin, erythropoeitin (EPO), interleukin-3, androgens, cyclosporin A, anti-thymocyte globulin (ATG) and metoclopramide (a drug often used to treat nausea). None of these trials was successful. Very low response rates in the form of a minimal increase in haemoglobin levels in DBA patients were achieved with metoclopramide. Its effect is mediated via the hormone prolactin.

A specific amino acid, L-leucine, was used in a major study in the USA to treat DBA patients after case reports of comprehensible haematological remissions of DBA. However, the study only produced very low response rates with less than 10% of patients treated exhibiting increases in haemoglobin levels. Some of the children exhibited some improvement in growth rate during the treatment phase.

There have recently been published individual case reports where DBA patients have been treated with elthrombopag, a thrombopoietin receptor agonist that was developed for the treatment of patients with chronic immune thrombocytopenia. These patients achieved independence from blood transfusions through treatment with elthrombopag, often at very high doses. However, there are no studies that confirm this effect in large patient populations or, above all, investigate side effects of long term treatment.

Research is currently underway for additional drugs to treat DBA.

Malformations

Many of the congenital malformations (such as thumb malformations or lower arm malformations) can be corrected by specific surgical procedures. Malformations in the internal organs (for example in the urinary tract, gastrointestinal tract or heart) can also be treated surgically. The interdisciplinary treatment team, together with the relevant specialists from surgery, cardiology, nephrology or gastro-enterology departments will advise individual patients which interventions are advisable and indicated.

Complications associated with the disease itself, as well as treatment-related complications, may occur in DBA patients. Transfusion therapy without iron chelation therapy causes severe iron overload that can manifest itself in the form of heart disease (such as cardiac insufficiency, cardiac arrhythmias), liver disease (such as hepatitis, jaundice, ascites, splenomegaly, haemorrhages, performance deficits, lack of concentration), diseases of the hormone glands (such as diabetes, restricted growth, delayed puberty, developmental disorders, fatigue) and increased bone fragility (osteoporosis). These complications can be avoided by early, well-controlled iron chelation therapy.

Multiple transfusions can rarely cause alloimmunisation. This is a condition where the patient’s immune system detects the foreign proteins on the surface of the donor’s red blood cells and produces antibodies to these proteins. This may mean that the next transfusion from the same or similar donors with the same foreign proteins can cause a severe transfusion reaction. This destroys the red blood cells and may even cause thrombosis (blood clots). There are situations where there is an ever decreasing set of suitable red blood cell concentrates that can be found for DBA patients with alloimmunisation and ultimately the only treatment option left is stem cell transplantation.

The pathogenesis of DBA is a disorder in blood cell production in the bone marrow. In rare cases the disorder is not limited to erythropoiesis but progressively affects the production of white blood cells and platelets. This is referred to as pancytopenia. A decreased white blood cell count can cause fever, mouth ulcers and severe infection whilst a low platelet count can lead to spontaneous skin and mucosal haemorrhages such as nosebleeds. SCT may also be indicated in these cases.

DBA is now also classified as a tumour predisposition syndrome, that is a disease where certain cancers occur more frequently or earlier than in people not affected by it. The precise type of cancers that occur more frequently and the additional level of risk of cancer are not yet known, although tumour clusters include breast cancer, bowel cancer, bone tumours and skin cancer. DBA patients are therefore advised to have an annual medical examination, to participate in available cancer screening programmes and consult a doctor at an early stage if symptoms occur. A specific recommendation for cancer screening of DBA patients cannot currently be made.

A few DBA patients exhibit signs of a weak immune system directly after birth or throughout their life, particular in adulthood. This may involve accumulation of infections, severe bacterial infections, infections due to “atypical” bacteria and persistent infections or infections with atypical progressions. Nevertheless, DBA patients are advised to obtain all recommended vaccinations including the influenza vaccine.

For reasons that are poorly understood, older adult patients may experience a decline in physical and mental performance. Patients report that their sports endurance is reduced in comparison with peers and concentration and memory problems occur earlier than expected. Data collection and a survey of adult DBA patients on this very important observation are currently being conducted via a online self-submission module.

With every blood transfusion, patients receive, in addition to the red blood cells they urgently need, the iron that is bound in those cells. Each red cell concentrate contains approximately 200 - 250 mg iron, whilst an individual on a balanced diet only consumes around 1 - 2 mg iron a day. Iron overload occurs when transfusions exceed approximately 10 - 15 red cell concentrates. Patients with anaemia also permanently absorb an excess of iron through their gut.

An iron overload means that iron can no longer be bound to its actual transport proteins and is stored in various organs, particularly the heart, liver and hormone-producing glands. This can cause severe organ damage, with heart damage being the most frequent cause of death in patients with congenital anaemia. Early diagnosis and measurement of the iron load is very important for patient prognoses.

The iron status in the blood can be measured by determining transferrin saturation and ferritin levels. Higher levels of iron saturation of the transport protein transferrin are an indication of iron overload. The ferritin level indicates how much iron is stored in the body’s organs, particular the liver. However, the ferritin level also increases during inflammation or infection and it therefore acts more as a course parameter that can only provide an imprecise indication of the extent of the iron overload. A far more precise measurement of iron overload can be obtained from a magnetic resonance imaging (MRI) scan of the organs affected, the liver, pancreas and heart. The MRI scanner measures the effect of the iron deposits on how the organs present; a liver with an iron overload shows up as much darker in an MRI scan than a healthy liver (see Figure 5).

The interaction between the magnetic iron and the MRI’s magnetic field (which is required for imaging) plays an important role here. An MRI scan is painless and does not involve radiation. An MRI scan used to determine iron overload should be conducted in one of the major centres for treatment of blood disorders since the scan results need to be evaluated by an interdisciplinary team of specialists in (paediatric) blood disorders and (paediatric) radiologists.

A liver biopsy can also be used to determine the iron concentration in the liver tissue directly. This involves inserting a special needle through the patient’s abdominal wall and removing a small amount of liver tissue under ultrasound guidance. This can cause complications such as haemorrhage, infections, bile leakage or inflammation. In children and adolescents the intervention is performed under full anaesthesia and requires in-patient monitoring. There is also a risk that the iron overload at the biopsy site is not a true reflection of the iron overload in the whole of the liver since distribution of the iron load in the liver is often patchy. Nowadays MRI scans are considered the gold standard for measuring iron levels in the liver, with liver biopsies reserved for additional queries (e.g. hepatitis, cirrhosis of the liver).

The option of measuring iron levels in organs using a SQUID (superconducting quantum interference device), which was used to determine very precise values for iron levels in organs over a long period, has recently become unavailable in Germany.

Treatment of patients with rare forms of anaemia should be carried out by an experienced centre for blood disorders. Regular tests should be performed at the centre to measure the iron overload and screen for potential complications of the iron overload. Early identification of complications considerably improves the chances of a successful treatment outcome. We have produced a checklist of the regular tests recommended for DBA patients (see Download section).

The human body cannot eliminate excess iron itself. Drug treatment to help flush the iron out of the body (iron chelation therapy) is therefore required. This uses chelators, substances that bond with the surplus iron to form a compound (chelate). The bonded surplus iron can then be excreted via urine and/or stools. Treatment should start after ferritin readings reach a specific level (in most cases 2 x readings >1000 ng/mL), the iron load in the liver tissue reaches a specific level (in most cases > 4.5 mg iron/g of dry weight of liver) or after approximately 10 - 15 transfusions. The international recommendation is that iron chelation therapy should not begin before the 2nd birthday.

There are currently three different iron chelators in use: deferoxamine (DFO, brand name Desferal®), deferasirox (DSX, brand name Exjade®) and deferipron (DFP, brand name Ferriprox®). Deferoxamine may be injected in three ways: through the skin (subcutaneously), muscle (intramuscular) or vein (intravenously). Deferasirox can be swallowed by patients as a tablet or ground powder (oral chelator). The oral chelator Deferipron is available for a few patients with DBA for whom treatment with Deferoxamin or Deferasirox is not an option. Which of the different chelators is used depends on age, individual side effects and of course how effective the drugs are in treating the iron overload in the various organs. Very intensive iron chelation measures may be required in patients with very severe iron overload and heart failure, cardiac arrhythmias or diabetes. In conclusion, iron chelation therapy should only be controlled and monitored by a specialist in blood disorders. We have produced a checklist of the additional regular tests recommended for patients undergoing iron chelation therapy (see Download section).

The quality of medical care provided has a huge effect on the prognosis for patients with DBA. Age-appropriate patient consultations, along with the opportunity for patient and relatives to be involved in care, play an important role here.

Almost all patients with Diamond-Blackfan anaemia (DBA) can successfully attend nursery and school, complete education or study, learn and practise a profession. Some patients (20-30%) even experience remission (where the anaemia spontaneously disappears) in the course of their life. The majority of patients, however, will permanently require steroid treatment or transfusions. The long-term prognosis for DBA patients may be restricted by complications from the transfusion therapy or excess doses of steroids. There is currently no way to assess how the increased cancer risk affects long-term survival rates.

It is yet not possible to predict how DBA will progress in individual patients. DBA may take an entirely unexpected course, even under the most favourable or unfavourable conditions. The overall life expectancy of DBA patients is not yet known. The disease was first described just 70 years ago and so there are not enough patients who have been observed over a long period. At the same time, there have been so many improvements in treatment over the last few decades (particularly treatment of iron overload) that the prognosis for all patients with congenital anaemia has improved considerably.

Since DBA is a highly complex disease there are numerous research questions that need an answer. The natural history of DBA is being recorded in numerous registers of DBA patients worldwide. Recording history in adult patients, their health and care status, as well as recording co-morbidities and cancers in later life form the focus of our current research. For this purpose we are currently developing a self-reporting online module that adult patients can use to submit their medical data themselves. We are currently learning from older DBA patients so that we can improve the therapy for young patients.

Even if a specific genetic alteration (pathogenic genetic variant) can be identified as disease causing in 70-80% of patients with clinical diagnosis of DBA, this still leaves a relevant proportion of patients for whom the alteration is yet to be identified. Identification of new pathogenic genetic variants causing DBA is being helped by the development of new functional tests that will allow DBA to be diagnosed even where there is no evidence of mutation. One possible method, but one not yet feasible for routine diagnostic testing, is human ribosome profiling. Ribosome profiles of patients with DBA are abnormal and differ from those of healthy human beings.

In order to understand how the disease disrupts haematopoiesis and why steroid therapy leads to remission of the anaemia in many but not all patients, the pathogenesis of DBA is being investigated in numerous laboratories around the world. One particularly important discovery was that the transcription factor GATA1, which is essential for erythropoiesis, cannot be produced properly as a result of the alteration of the ribosomes in DBA patients. Interestingly, patients with a congenital GATA1 mutation have a disease that is very similar to the classic form of DBA.

Since allogeneic stem cell transplantation continues to be the only curative treatment option for DBA patients, so that it is only the haematological problems and not other organ damage that can be treated, there is ongoing intensive research into other drugs for treating the disease. There are now large, highly IT-intensive platforms in existing that are searching for molecules that can restore ribosome function. Drugs that are approved for other diseases are also already undergoing testing on DBA patients in clinical trials, including elthrombopag in a US study.

With respect to allogeneic stem cell transplantation, clinical trials to identify the best time for and the best form of conditioning, i.e. preparatory chemotherapy prior to SCT, for DBA patients are underway.

As already mentioned in the “treatment methods for DBA patients”, the gene therapy in DBA patients with a pathogenic genetic alteration in the RPS19 gene is currently being developed. This initially requires in vitro experiments, although the principle of gene therapy for congenital anaemias has already been tested successfully in the form of Fanconi anaemia, a disease that can also be associated with abnormalities and bone marrow failure.